About half of stroke patients present with penumbra, defined as the tissue immediately surrounding an ischemic area in which blood flow is compromised due to vascular occlusion. The penumbra tissue may remain viable for several hours after an ischemic event due to collateral vessels that provide sufficient oxygen and nutrients to maintain neuronal structure but not enough to support function. As time elapses after stroke onset, the scarcity of oxygen supply causes the penumbra tissue to infarct, resulting in neurological deterioration. Omniox has engineered a safe first-in-class oxygen carrier (OMX) that improves brain oxygenation after stroke to preserve the neuronal and glial cell network viability within the oxygen-deprived penumbra tissue, resulting in the amelioration of neurological function. Because there is a high unmet need for therapeutics that preserve penumbra viability in stroke patients, OMX is a promising therapeutic candidate. In SBIR Phase I studies, Omniox has successfully achieved each of the milestones set out in accordance with the Stroke Therapy Academic Industry Roundtable (STAIR) and RIGOR guidelines demonstrating: 1) accumulation of OMX in the oxygen-deprived brain areas in stroke models of transient and permanent occlusion of the middle cerebral artery (tMCAO and pMCAO), 2) penetration of OMX into the brain parenchyma of the larger brain of a dog stroke patient; 3) sustained improvement of brain oxygenation and reduction of brain cell death; 4) prevention of infarct growth and long-term increase of neuronal survival; 5) significant amelioration of sensorimotor function in aged rats for at least a month after stroke onset. Importantly, OMX is efficacious in tMCAO stroke models in which penumbra exists. Therefore, these data support clinical translation of OMX in a well-defined patient population in which penumbra tissue can be salvaged using mechanical devices that remove the clot and restore blood flow. Since penumbra is detected in a majority of ischemic stroke patients, OMX could fundamentally change the landscape of stroke treatment. This Phase ll proposal builds upon our Phase I data to further explore the potential of OMX to benefit an expanded patient population presenting salvageable penumbra as well as complete additional STAIR criteria to demonstrate the translational potential of OMX. To do so, we will test OMX in multiple species and stroke models with varying spatio-temporal profiles of penumbra and infarct volume that mimic a range of clinical stroke scenarios such as: 1) a permanent occlusion model to support treating patients ineligible for recanalization (Aim 1), 2) a clot-based model to mimic thrombolytic recanalization with IV tPA in patients (Aim 2), and 3) a transient occlusion model in a non-human primate model with a large gyrencephalic brain suitable for longitudinal imaging to model the complexity of the human brain (Aim 3). These Phase II studies will guide the dose, therapeutic window, and selection of patient population for future clinical trials. CONFIDENTIAL (c)2015 Omniox, Inc. For review purposes only.